The histone deacetylase inhibitor SAHA exerts a protective effect against myocardial ischemia/reperfusion injury by inhibiting sodium-calcium exchanger

• Published in: Biochemical and biophysical research communications 2023-09, Vol.671, p.105-115
• Main Authors: Shi, Xiaocui, Yin, Yajuan, Guo, Xuwen, Liu, Mei, Ma, Fangfang, Tian, Li, Zheng, Mingqi, Liu, Gang
• Format: Article
• Language: English
• Subjects: Apoptosis; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; CaMKII; Histone deacetylase inhibitor; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Humans; Myocardial ischemia/reperfusion; Myocardial Reperfusion Injury - drug therapy; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - prevention & control; Myocytes, Cardiac - metabolism; Na+-Ca2+ exchanger; Sodium-Calcium Exchanger - metabolism; Vorinostat - pharmacology
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2023.05.120

Calcium overload performs a crucial function in the pathogenesis of myocardial ischemia-reperfusion (I/R) damage, which contributes to mitochondrial impairment and apoptosis of cardiomyocytes. Suberoylanilide hydroxamic acid (SAHA), a small molecule histone deacetylases inhibitor with modulatory capacity on Na+-Ca2+ exchanger (NCX), is proven to have protective potential towards cardiac remodeling and injury, but the mechanism remains unclear. Hence, Hence, our present research explored the modulation of NCX-Ca2+-CaMKII by SAHA in myocardial I/R damage. Our outcomes indicate that in vitro hypoxia and reoxygenation models of myocardial cells, SAHA treatment inhibited the increase in expression of NCX1, intracellular Ca2+ concentration, expression of CaMKII and self-phosphorylated CaMKII, and cell apoptosis. In addition, SAHA treatment improved myocardial cell mitochondrial swelling inhibited mitochondrial membrane potential diminution and the openness of the mitochondrial permeability transition pore, and protected against mitochondrial dysfunction following I/R injury. In vivo, SAHA treatment alleviated the decrease in FS% and EF%, the increase in the myocardial infarct area, and myocardial enzyme levels caused by I/R injury, while also reducing myocardial cell apoptosis, and inhibiting mitochondrial fission and mitochondrial membrane rupture. These results indicated that SAHA treatment alleviated myocardial cell apoptosis as well as mitochondrial dysfunction resulting from myocardial I/R impairment, and contributed to myocardial function recovery by inhibiting the NCX-Ca2+-CaMKII pathway. These findings offered additional theoretical support to explore the mechanism of SAHA as a therapeutic agent in cardiac I/R damage and develop new treatment strategies. •Novel mechanism: SAHA intervention ameliorates myocardial ischemia/reperfusion damage by targeting NCX-Ca2+-CaMKII.•SAHA demonstrates cardioprotective effects by targeting Ca2+ homeostasis and mitochondrial dynamics.•SAHA treatment preserves mitochondrial integrity and function during myocardial ischemia/reperfusion injury.•Mechanistic insights provided into SAHA therapeutic potential for ischemic heart disease and future treatment strategies.